Abstract LB134: Pre-clinical development of a masked tumor activated nectin-4 conditional IL-15 immuno-cytokine (ABBV-622)

Abstract Cytokine therapies have been shown to be efficacious but are largely limited in their utility due to toxicity issues. Systemic IL-15 is not well tolerated in humans as it induces CRS in patients with melanoma and renal cancer. To address systemic toxicity, we have designed a nectin-4 targeted IL-15 conditional immuno-cytokine (IC) that limits systemic bioactivity and targets IL-15 to the tumor microenvironment (TME). The hypothesis that tumor targeted IL-15 will enhance anti-tumor efficacy is supported by data that demonstrates ∼ 80 % complete response rate of intravesicular Anktiva® in bladder cancer. Additionally, nectin-4 has also emerged as a promising target for patients with bladder cancer as PADCEV® recently received accelerated approval from the FDA. ABBV-622 is a nectin-4 k-in-h Ab that carries IL-15 on one heavy chain and a MMP cleavable linker and IL-2Rβ mask on the other heavy chain. The MMP cleavable linker allows conversion of inactive to active IL-15 by proteases that are preferentially active in the TME. ABBV-622 shows a desirable profile to increase the magnitude of CD8+ T and NK cell proliferation, IFNγ secretion and STAT5 signaling in human PBMCs only following MMP-mediated cleavage of the IL-2Rβ mask. ABBV-622 induces CD8+ T and NK cell proliferation and cytokine/chemokine release from lymphocytes of tumor patient derived explants while minimal bioactivity has been observed in blood from cancer patients. In vivo studies demonstrate the tumor growth inhibitory activity of ABBV-622 with good tolerability in humanized mouse xenograft models. In addition, this IC shows significant tumor uptake, and an immunologically driven mechanism in the tumor by inducing activation, proliferation, and cytotoxicity of NK, CD8+ and γδ T cells. Pharmacokinetic studies in mice show a high ratio of the cleaved to total ABBV-622 in tumor vs circulation. ABBV-622 is an innovative therapeutic approach that has the potential to improve the response across nectin-4 expressing tumors in the clinic. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. No honoraria or payments were made for authorship. Citation Format: Nicole Belmar, Sarah Chan, Sun Ho, Hsi-Ju Wei, Michelle Chen, Angeline Dang, Xu Shi, Susan Rhodes, Edgar Ramirez-Montiel, Arash Shemirani, Aditi Prashar, Travis Durkin, Charles Forsyth, David Powers, Wendy Ritacco, Pragya Shah, Yinusa Abadat, Xiao He, Enrico DiGiammarino, Ramesh Iyer, Joel Tan, Jos Campbell, Suzanne Ybarra, Vivian Zhao, Yuni Fang, Flora Lo, Yoshiko Akamatsu, John Engelhardt, Hamsell M. Pre-clinical development of a masked tumor activated nectin-4 conditional IL-15 immuno-cytokine (ABBV-622) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB134.